The introduction of unique chemical transformations can considerably shorten synthetic pathways toward medicinally important compounds. Cycloadditions are known to be especially powerful reactions for building molecules of high complexity. The objectives of this proposal are to develop and use new cycloadditions of cyclobutadiene. It will be shown that highly functionalized cyclobutenes generated through intramolecular cyclobutadiene cycloadditions can provide a versatile platform for rapid entry into complex molecular systems. In particular, when used with other key transformations, the molecular complexity and structural strain of the cycloadducts offer unique opportunities for the efficient construction of medium ring-containing natural products with intriguing biological activities. The cyclobutene cycloadducts will be used in the preparation of cycloheptanoid and cyclooctanoidcontaining products. Inter- and intramolecular cyclopropanations of the cyclobutenes, followed by selective carbon-carbon bond fragmentations, will be used to generate effectively the 5-7 ring system found in numerous biologically active natural products. Similarly, a (2+2) photocyclization/fragmentaton strategy will provide access to the 5-8-5 ring system. Concise applications of the chemistry toward the synthesis of diterpenes, such as kalmanol, are detailed. In short, the combination of developing new routes toward cyclobutadiene complexes, investigating novel cycloadditions of these complexes, and demonstrating the utility of the cycloadducts in medium ring synthesis will offer improved opportunities for building molecules of biological significance.